The long-range goal of this project is to contribute to our understanding of the causes and control of diabetes mellitus. The immediate goals are to synthesize pure, crystalline glucagon and carefully selected analogs of glucagon that will cause predictable changes in the conformation of hormone. These structural changes will be based on the Chou-Fasman rules. With this information, and several leads from the literature, we hope to be able to design and synthesize glucagon analogs that will function as inhibitors of the hormone. Such inhibitors are expected to aid in studies on the mechanism of action of glucagon and to provide an agent for the in vivo regulation of glucagon activity, which will lower the level of insulin required for the control of diabetes. We have recently succeeded in synthesizing active pancreatic glucagon in crystalline form by means of solid phase peptide synthesis. Our aim is to complete the purification and characterization of this product and to use similar methodology for the synthesis of the proposed analogs. Only two previous syntheses of glucagon have been achieved. These made use of much more difficult and time consuming methods, and in spite of a ten-year lapse of time since the first synthesis, no synthetic analogs of glucagon have been reported. We believe our new methods will enable the relatively rapid and simplified synthesis of many of the required products.